Streptococci are the predominant species to initially adhere to the salivary pellicle (Diaz et al., 2006). In supragingival plaque, predominantly the dietary intake of sugars promotes the formation of extracellular polymeric substances (EPS) and acidic metabolites causing the resident microflora to shift towards aciduric and acidogenic species (Lamont et al., 2018). If persistent, this leads to the acidification of the biofilm microenvironment and, ultimately, to the demineralization of dental enamel and the development of carious lesions (Lamont et al., 2018). The role of mutans streptococci (MS), i.e., S. mutans and S. sobrinus, as cariogenic agents has long been recognized (Conrads et al., 2014; Hajishengallis et al., 2017). The cariogenic potential of MS stems from three characteristic traits – the species’ ability to synthesize large quantities of extracellular glucan from sucrose, their ability to metabolize a wide range of carbohydrates into organic acids, i.e., their acidogenicity, and their tolerance towards environmental stress conditions such as low pH, i.e., their aciduric nature (Lemos et al., 2019). Extracellular glucans form essential building blocks of the EPS as part of the extracellular biofilm matrix, which confers to the bacteria protection from shear forces and resistance to antimicrobials, influences the diffusion of oxygen, nutrients, quorum sensing signals and metabolites, and creates an acidic microenvironment in which commensal bacteria are outcompeted by cariogenic species (Bowen et al., 2018).

Carious lesions or other factors that damage the tooth’s integrity can reach the dental pulp, which is principally encased in the root canal system, exposed to the bacteria present in the oral cavity. Bacterial colonization elicits inflammation and necrosis of the dental pulp as well as inflammation of the periapical region, finally leading to bone resorption and the formation of granulomas or cysts (Graves et al., 2011). Oral streptococci, such as S. oralis, S. anginosus, S. mitis, S. sanguinis (Chávez de Paz et al., 2005; Narayanan and Vaishnavi, 2010), and S. mutans (Lima et al., 2020) are frequently among the species detected in root canal infections. In the dental pulp, bacterial pathogen associated molecular patterns (PAMPs) are recognized by macrophages, dendritic cells (DCs), odontoblasts and endothelial cells, and elicit an immune response leading to the recruitment of specialized immune cells and the initiation of bacterial clearance (Khorasani et al., 2020). The inflammatory response mechanisms, cytokine networks as well as pulpal disease pathogenesis are the focus of other reviews (Hahn and Liewehr, 2007a; Farges et al., 2015; Khorasani et al., 2020; Galler et al., 2021).

The onset of gingivitis and emergence of periodontal diseases is caused by the shift in the composition of the resident oral microbiota from commensal to dysbiotic (Hajishengallis and Lamont, 2012). In a healthy individual, bacteria in the subgingival crevice exist in a balanced state with the host immune system, under controlled, low-level inflammation keeping bacterial growth in check (Hajishengallis and Lamont, 2016). This symbiotic state can be disrupted if certain risk factors, such as disadvantageous host genetics or lifestyle, or systemic diseases apply, or if keystone pathogens are present (Loos and Van Dyke, 2020). Dysbiosis is characterized by an increase in bacterial mass and the prevalence of Gram-negative, anaerobic species, leading to chronic inflammation (Hajishengallis et al., 2020). Particularly, the emergence of inflammophilic species such as Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Aggregatibacter actinomycetemcomitans or Filifactor alocis (Haffajee et al., 2008; Könönen et al., 2019), their modulation of the immune response and interaction with the resident polymicrobial community support an exacerbation of inflammation and bacterial overgrowth (Hajishengallis et al., 2012). Periodontal pathogens are capable of evading (Hajishengallis, 2011; Bloch et al., 2018, 2019) and subverting (Hajishengallis and Lamont, 2014; Hajishengallis and Diaz, 2020) the host immune response and thereby dysregulate immune homeostasis. A detailed description of immune mechanisms in the context of periodontal diseases can be found in several excellent reviews (Hajishengallis, 2014; Ebersole et al., 2017; Könönen et al., 2019).

Oral streptococci regulate the structure and function of the oral microbiome in a way that is beneficial to human health (Baty et al., 2022). However, Streptococcus was determined by metagenomic analyses as the predominant genus in patients with gingivitis (Park et al., 2015). As pioneer colonizers, streptococci not only enable later colonizers and pathogenic species to co-adhere, they also can be considered as accessory pathogens, as is the case for S. gordonii whose interaction with P. gingivalis and A. actinomycetemcomitans was found to substantially elevate these species’ pathogenicity (Kuboniwa et al., 2006; Daep et al., 2011; Ramsey et al., 2011). In pathogen-free mice, inoculation with P. gingivalis led to a massive increase in streptococcal cell numbers (Hajishengallis et al., 2011) and in an in vitro subgingival biofilm model, omission of the periodontal pathogen from the community resulted in invasion of gingival epithelial cells by S. oralis instead (Thurnheer et al., 2014). On the other hand, P. gingivalis failed to cause periodontal disease in germ-free mice in the absence of the commensal core microbiome –which in fact was capable of causing modest bone loss in germ-free mice on its own putting oral streptococci in the spotlight as modulators of oral immune responses (Hajishengallis et al., 2011; Abusleme et al., 2013). These findings highlight the central role oral streptococci play in the balancing act between the maintenance of host-microbiome homeostasis during health and immunomodulatory effects in disease. In the following sections, the factors employed by these bacteria to tip this balance towards a healthy or diseased state will be discussed.

AgI/II adhesins are widely distributed among oral streptococci and constitute an important factor in the bacteria’s pathogenicity and ability to colonize oral sites (Jenkinson and Demuth, 1997) (see 5.). The AgI/II proteins consist of several structural regions, with the intertwined A- and P-regions presenting the globular, less conserved V-domain on the cell surface for ligand interaction (Manzer et al., 2020). Viridans streptococci reportedly induce the expression of proinflammatory cytokines IL-8 and IL-6 in endothelial and IL-8 in epithelial cells; in the case of S. mutans OMZ175, this is facilitated through the binding of AgI/II (as well as rhamnose-glucose polysaccharide (RGP) – see 7.3.) to glycoproteins present at the host cell surface through lectin-type interactions (Vernier et al., 1996). IL-8 stimulation occurs through binding of AgI/II to α5ß1 integrin and subsequent activation of MAPK signaling (Al-Okla et al., 1999). In primary human coronary artery endothelial cells, cellular binding of AgI/II was furthermore shown to stimulate the expression of the adhesion molecules E-selectin, ICAM-1 and VCAM-1 and thereby stimulate trans-endothelial migration of neutrophils and contribute to the exacerbation of inflammatory responses to the bacterial burden (Vernier-Georgenthum et al., 1998). Also, binding of AgI/II to monocytes occurs via a lectin-type interaction with Sia and fucose residues exposed on host cell surface-glycoproteins and results in an increased production of the proinflammatory cytokines TNF-α, Il-1β and Il-6 (Soell et al., 1994; Chatenay-Rivauday et al., 1998, 2000). Induction of pro-inflammatory cytokines in synovial cells suggests that AgI/II might even play a role in rheumatic disease, its initiation and perpetuation (Gourieux et al., 2001). Stimulation of TNF-α in THP-1 cells by the extended V-region of AgI/II was observed not only for S. mutans strains, but also for S. gordonii and the SAG members S. anginosus, Streptococcus intermedius and Streptococcus constellatus, highlighting the universal role the AgI/II protein family plays in streptococcal adhesion and virulence (Chatenay-Rivauday et al., 2000).

Another factor contributing to S. mutans’ success not only within but also outside its ecological niche is the cell surface glycoprotein Cnm which exhibits collagen- and laminin-binding capability. Cnm is present in 10-20% of all isolated strains of S. mutans (Nakano et al., 2010) and was most extensively studied in the S. mutans strain OMZ175. Cnm was found to be vital for the invasion of human coronary artery endothelial cells (HCAEC) and virulence in a Galleria mellonella infection model (Abranches et al., 2011; Aviles-Reyes et al., 2014). In the oral cavity, Cnm promotes S. mutans’ invasion of oral keratinocytes and fibroblasts and enhances binding of the bacterium to collagenated surfaces, as well as dentin and root tissues contributing to its cariogenicity (Miller et al., 2015). Furthermore, Cnm was found to influence bacterial cell permeability and therefore might play a role in the susceptibility to antimicrobial agents (Naka et al., 2022).

Together with AgI/II, Cnm plays a crucial role in the aggravation of non-alcoholic steatohepatitis (NASH) (Naka et al., 2014, 2016, 2018); it is directly involved in and a potential risk factor for hemorrhagic stroke (Nakano et al., 2011) and IE (Nomura et al., 2013) and therefore can be considered as an indispensable virulence factor in the onset and progression of systemic diseases such as IE elicited by Cnm-positive S. mutans strains. Cnm is most frequently found in strains with serotype f (see 7.3.), such as S. mutans OMZ 175, which in contrast to serotype c strains, is not most common in dental plaque, but has been specifically implicated in the pathogenesis of systemic disease (Abranches et al., 2011).

S. mutans decorates its cell surface with a rhamnose-glucose polysaccharide (RGP), a major cell wall antigen whose composition determines the strain serotype (c, e, f, and k) and which has distinct functions in cell division and morphology (Rijn and Bleiweis, 1973; Nakano and Ooshima, 2009; De et al., 2017). Also, in colonization of tooth surfaces - as well as heart muscle and kidney tissues - serotype f RGP plays a role as a putative adhesin (Stinson et al., 1980; Engels-Deutsch et al., 2003). The RGP’s contribution to adhesion was also demonstrated for THP-1, dental pulp and periodontal ligament cells, which upregulated the production of IL-6 and IL-8 in response to bacterial challenge dependent on the presence of RGP as well as AgI/II on the cell surface (Engels-Deutsch et al., 2003). RGP binds to human monocytes in a CD14-dependent manner and induces the release of TNF-α and other pro-inflammatory cytokines (Benabdelmoumene et al., 1991; Soell et al., 1995) as well as the up-regulation of RFc γ (Benabdelmoumene et al., 1991). RGP derived from S. mutans OMZ175 binds epithelial as well as endothelial cells in a dose-dependent manner and stimulates the release of IL-8 and IL-6 (Vernier et al., 1996). In rat model studies, RGP was found to render S. mutans more virulent in the induction of IE (Nagata et al., 2006) and stimulate nitric oxide synthase activity linking it to the genesis of septic shock induced by Gram-positive bacteria (Martin et al., 1997). Furthermore, the hydrophilic nature of RGP might play a role in the resistance of S. mutans to phagocytosis by PMNs and thereby contribute to the bacteria’s defiance of immune response mechanisms and survival within the host (Tsuda et al., 2000).

In Gram-positive bacteria, teichoic acids – wall teichoic acids (WTA) anchored to the cell wall peptidoglycan and lipoteichoic acids (LTA) anchored to membrane glycolipids - constitute a major part of the cell envelope and play vital roles in bacterial physiology, surface attachment, as well as interspecies and host interactions (Silhavy et al., 2010). Depending on the chemical structure, LTAs can be classified into five types (I-V) (Percy and Gründling, 2014). Type I, present e.g., in S. mutans and S. gordonii, is comprised of repeating polyglycerolphosphate units coupled with D-alanine and glucose (Lima et al., 2019); type II LTA as present in S. oralis, is composed of polyribitolphosphate repeating units (Hong et al., 2014a).

In the context of cariogenesis, LTA plays a vital role in conferring adhesive properties to bacterial cells and hydration of the cariogenic plaque in concert with streptococcal derived glucan (Rølla et al., 2009). When provided with high amounts of sucrose, S. mutans upregulates not only its glucan production, but also produces higher amounts of LTA (Rølla et al., 2009). S. mutans LTA furthermore induces apoptosis in pulpal cells from deciduous teeth indicating its involvement in the development to pulpitis (Wang et al., 2001), which has been reviewed elsewhere (Hahn and Liewehr, 2007b). In monocytic, dental pulp and periodontal ligament cells, S. mutans LTA is a less potent inducer of proinflammatory cytokines than RGP and AgI/II (Engels-Deutsch et al., 2003). In a murine macrophage cell line, LTA from both S. mutans and S. sanguinis induced the production of TNF-α and release of nitric oxide (NO) potentially contributing to septic shock elicited by these bacteria in immunocompromised patients (English et al., 1996; Hong et al., 2014a).

When analyzing S. mutans LTA-binding proteins in saliva of caries-free and caries-active subjects, Hong and coworkers found differences in protein profiles dependent on the health status, with histone H4, neutrophil defensin-1 and profilin-1 being associated with health, and cystatins and lysozyme, among others, predominantly present in saliva from caries patients (Hong et al., 2014b). In the case S. sanguinis, LTA was shown to antagonize recognition of lipopolysaccharide (LPS) on gingival fibroblasts in a CD14-dependent manner, thereby potentially dampening the cells’ immune response to Gram-negative periodontal pathogens and contributing to commensalism (Sugawara et al., 1999). LTA in contrast to LPS also stimulates expression of hepatocyte growth factor/scatter factor in gingival epithelial cells (Sugiyama et al., 1996). When stimulated with an LTA-deficient strain of S. gordonii, human dendritic cells reacted with a stronger immune response, i.e., increased phagocytic activity and production of proinflammatory markers and T-cell activation, than those treated with the corresponding parent wild-type strain, indicating an immune evasive role of LTA (Kim et al., 2023). In this context it is interesting to note, that S. gordonii cell wall lipoproteins, but not LTA have been shown to stimulate IL-8 production in periodontal ligament cells in a TLR2-dependent fashion (Kim et al., 2017; Park et al., 2020) and, in the case of lipoprotein PpiA, to suppress phagocytosis by macrophages (Cho et al., 2013).

Colonization of the oral cavity by oral streptococci depends on the production of extracellular glucans that to a large part make up the ECM of streptococcal biofilms (Nobbs et al., 2015; Bowen et al., 2018). S. mutans produces several dietary sucrose-hydrolyzing enzymes producing fructose and glucose, which are the building blocks of α-1,2- and β-1,6-linked glucans formed by the subsequent action of secreted (GtfD) and cell-wall associated (GtfB, GtfC) glucosyltransferases (Gtfs) (Nobbs et al., 2015; Bowen et al., 2018). In cariogenic biofilms, these sugars contribute to the acidification of the biofilm microenvironment and the shift to a dysbiotic microbiota, since these are catabolized along fermentative pathways leading to acid production (Bowen et al., 2018; Lamont et al., 2018). The secretion and action of Gtfs is not a specific trait of S. mutans, in which these enzymes have been most extensively studied; many oral streptococci employ Gtfs for colonization, adhesion, cohesion, and interbacterial interactions (Nobbs et al., 2009; Abranches et al., 2018). GtfB, GftC and GtfD adhere to the salivary pellicle on the tooth surface as well as to other microorganisms including bacteria and Candida albicans, essentially converting them to glucan producers contributing to the build-up of EPS and biofilm formation (Falsetta et al., 2014; Bowen, 2016). Furthermore, glucan binding proteins (Gbps) expressed by MS are prerequisites for successful biofilm formation, facilitating binding to dextrans and accumulation of MS in the biofilms (Nobbs et al., 2009). Streptococcal Gtfs can be regarded as immunogenic; a humoral immune response with anti-Gtf-specific immunoglobulin G (IgG) in serum or IgA in saliva naturally occurs in human populations (Chia et al., 1997). A Gtf-inhibitory factor (GIF) was found as an innate defense factor present in human saliva, specifically binding to the glucan binding domain of Gtfs and inhibiting Gtf function (Jespersgaard et al., 2002). GtfC and GtfD influence T-cell proliferation and modulate the immune response by monocytes, with a higher response elicited by GtfD than GtfC (Chia et al., 2001). S. mutans Gtfs furthermore robustly induce the production of IL-6 by T-cells in vitro as well as in vivo in a experimental rat model of endocarditis – pinpointing their contribution to disease development outside the oral cavity, since IL-6 levels were found to be elevated in patients with IE (Chia et al., 2001). In the same experimental model, it was also shown that S. mutans Gtfs induce the production of IL-6 in endothelial cells in infected heart valves, specifically during the acute stage of infection (Shun et al., 2005). In S. gordonii, a Gtf contributes to the bacterium’s capability to cause IE, being a prerequisite for the adhesion to endothelial as well as epithelial cells in vitro (Vacca-Smith et al., 1994).

In the resolution of bacterial infection, neutrophils play a pivotal role, clearing and killing bacterial invaders through phagocytosis, granule release, oxidative burst, and neutrophil extracellular trap (NET) formation – the release of chromatin fibers carrying antimicrobial peptides (AMPs) ready for bacterial killing and prevention of bacterial spreading (Scott and Krauss, 2012; Chapple et al., 2023). In S. sanguinis, a streptococcal wall-anchored nuclease (SWAN) confers resistance to NET killing by digesting released NET DNA (Morita et al., 2014). Another S. mutans nuclease - DeoC - enables the bacteria to escape NETs and facilitates biofilm dispersal (Liu et al., 2017). Lacking the LPxTG sorting motif for cell wall anchoring, DeoC most likely acts during late stages of biofilm growth when cell autolysis and dispersal occur and aids in bacterial escape of entrapment in NETs by chromatin degradation (Liu et al., 2017).

One characteristic trait of oral streptococci that has been getting attention for its relevance in the regulation of immune responses is the production of hydrogen peroxide as a by-product of aerobic metabolism (Zhu and Kreth, 2012). Through the production of H₂O₂, oral streptococci like MGS inhibit other potentially pathogenic species, among them S. mutans, and thereby gain a competitive advantage over these species (Kreth et al., 2008). By triggering the release of eDNA, H₂O₂ production additionally facilitates the exchange of genetic material between the bacteria (Kreth et al., 2009). In the interaction with the host, H₂O₂ production shows the potential to be a vital contributor to disease pathogenesis. Bacterial species such as S. sanguinis and S. oralis induce the formation of foam cells, contributing to atherosclerosis, and cause lysosome dysfunction and cell death in macrophages as well as in epithelial cells through the action of ROS, i.e., the release of H₂O₂ (Okahashi et al., 2011, 2013, 2014, 2016). Microarray studies of macrophages infected with S. oralis wild-type and a corresponding streptococcal pyruvate oxidase (spx)-deletion mutant deficient in H₂O₂ production showed that H₂O₂ suppresses the expression of proinflammatory mediators, especially NF-κB signaling, and cellular stress responses (Matsushima et al., 2017). Pyruvate oxidase SpxB catalyzes the conversion of inorganic phosphate and pyruvate to acetyl phosphate, carbon dioxide and H₂O₂ (Chen et al., 2011). Notably, SpxB is distinct from the S. mutans transcriptional regulator Spx, encoding two homologues, SpxA1 and SpxA2, involved in oxidative stress response and regulation of genes involved in cell division and cell envelope biosynthesis, respectively (Baker et al., 2020; Ganguly et al., 2020). S. oralis was furthermore found to inhibit the activation of inflammasomes through the release of H₂O₂ corroborating its contribution to the establishment and persistence of the oral commensal within the oral cavity and even in bloodstream infections (Erttmann and Gekara, 2019). In the context of periodontal disease, SpxB of S. oralis and S. mitis plays a vital role in enabling bacterial colonization and host homeostasis by inhibiting NF-κB signaling through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) (Tang et al., 2022). Also, through the induction of cell death in periodontal ligament cells (PDLs) by H₂O₂ production, S. gordonii, S. mitis, S. sanguinis and S. sobrinus play their part in the development of apical periodontitis (Park et al., 2021). In S. sanguinis, Spx was a prerequisite for bacterial survival in blood and an spx-deletion mutant failed to induce cell death and NET formation in neutrophils (Sumioka et al., 2017). Through the release of H₂O₂, oral streptococci can additionally dampen the proinflammatory immune response to LPS and F. nucleatum thereby influencing overall plaque development (Tang et al., 2022).

Genome mining studies have revealed an abundance of bacterial biosynthetic gene clusters (BGCs) in the oral microbiome producing small molecules and secondary metabolites that can function as signaling molecules and serve as language of interbacterial, interspecies and interkingdom communication (Donia and Fischbach, 2015; Liu et al., 2016; Aleti et al., 2019). Among these secondary metabolites are mutanobactins, mutanamide and mutanofactins - lipopeptides produced by S. mutans along a non-ribosomal peptide synthetase–polyketide synthase (NRPS–PKS) assembly line (Wu et al., 2010; Zvanych et al., 2015; Li et al., 2021). Mutanobactins act as interkingdom signaling molecules by blunting hyphae formation and inhibiting biofilm formation by the opportunistic pathogen C. albicans and as interspecies communicator by inhibiting planktonic growth of other oral bacteria (Joyner et al., 2010; Wu et al., 2010; Wang et al., 2012; Pultar et al., 2021). Given that, co-infection with S. mutans and C. albicans not only resulted in a higher bacterial-fungal burden, but also increased biofilm virulence and led to more severe carious lesion in a rat model (Falsetta et al., 2014), hyphae blunting by mutanobactin represents only a small facet of this highly complex interkingdom interaction and the implications of this process in vivo have yet to be determined. Interestingly, Zvanych et al. attested to the mutanobactins also immunomodulatory properties, since in a murine macrophage cell line pre-stimulated with LPS, mutanobactin B upregulated IL-6 and IL-12 and downregulated MCP-1, G-CSF and TNF-α production (Zvanych et al., 2015). Another small molecule produced by S. mutans with the potential to inhibit competing oral bacteria, is the tetramic acid mutanocyclin (Tang et al., 2020). In a Matrigel plug assay, mutanocyclin was found to inhibit CD45⁺ leukocyte infiltration thereby exerting an anti-inflammatory role (Hao et al., 2019).

For the development of microbial communities, quorum sensing (QS) is an indispensable mechanism of bacteria to regulate inter- and intra-species interactions. S. mutans utilizes multiple QS systems to regulate biofilm formation, transfer of genetic material and stress tolerance responses; one of these systems relies on the competence stimulating peptide (CSP) encoded by the comCDE gene locus (Bernabè et al., 2022). Medapati and coworkers recently explored the possibility that S. mutans CSPs might be recognized by bitter taste receptors (T2Rs) - G-protein coupled receptors (GPCRs) involved in taste chemosensation and recognition of bacterial QS molecules – thereby participating in innate immune responses to bacterial colonization (Medapati et al., 2021). The researchers demonstrated binding of CSP-1 to T2R14 expressed in gingival epithelial cells (GECs) and mediating activation of IL-6, IL-8 and TNF-α production, thus, identifying a novel mechanism of host-QS interaction and a potential target for therapeutic intervention (Medapati et al., 2021).

Due to their co-adhesion with P. gingivalis, MGS can be classified as accessory pathogens and contribute to the formation of pathogenic oral communities (Whitmore and Lamont, 2011). The formation of heterotypic communities between the different species has been extensively studied for S. gordonii and S. oralis with P. gingivalis. Cohesion occurs through the binding between P. gingivalis fimbriae Mfa1 and FimA to the streptococcal surface antigens SspA/B and surface-expressed glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively (Bergmann et al., 2004; Kuboniwa and Lamont, 2010). Upon binding, a signaling cascade is triggered in P. gingivalis, leading to the suppression of Mfa1 production and the expression of a protein tyrosine phosphatase Ltp1 which regulates protease activity and thereby influences the bacterium’s pathogenic potential (Maeda et al., 2008; Kuboniwa and Lamont, 2010; Hajishengallis and Lamont, 2014).

Another species that S. gordonii is frequently associated with is F. nucleatum (Mutha et al., 2018). Co-aggregation not only results in transcriptional changes within both bacteria, but also affects their survival within macrophages and decreases the expression of pro-inflammatory cytokines and thereby influences bacterial virulence and host persistence (Liu et al., 2021). Also the commensal S. cristatus dampens the response to F. nucleatum infection by inhibiting NF-κB and IL-8 production in oral epithelial cells (Zhang et al., 2008 ; Zhang et al., 2011).

Co-infection studies with S. oralis and C. albicans demonstrated that in an oral thrush mouse model, C. albicans augments streptococcal colonization and that, in turn, S. oralis contributes to the exacerbation of the immune response through TLR2 signaling and neutrophil recruitment causing more severe lesions than the opportunistic fungal pathogen alone (Xu et al., 2014). In epithelial tissues, the synergy between the two bacteria caused upregulation of pro-inflammatory markers (Martorano-Fernandes et al., 2023) and the disruption of epithelial barrier integrity through activation of calpain 1, a calcium ion–dependent cysteine protease specifically cleaving E-cadherin (Xu et al., 2016). Interaction with the allegedly harmless commensal S. oralis therefore seems to be a key contributor to C. albicans virulence and tissue invasion.

When oral keratinocytes were precultured with S. cristatus, S. salivarius, S. mitis or S. sanguinis, the presence of the oral streptococci inhibited keratinocyte colonization by A. actinomycetemcomitans, with S. sanguinis exerting the strongest inhibitory effect (Teughels et al., 2007; Sliepen et al., 2009b). In a similar experiment, adhesion of periodontal pathogens, including P. gingivalis, Prevotella intermedia and A. actinomycetemcomitans, to the surface of a parallel plate flow chamber was found to be reduced in the presence of a similar set of commensal streptococci, identifying antagonistic functions that could render these bacteria suitable candidates as probiotics in the prevention of periodontal disease recurrence (Van Hoogmoed et al., 2008). Different strains of S. salivarius alone reduced the secretion of IL-6 and IL-8 by gingival fibroblasts, which is usually induced by P. gingivalis, A. actinomycetemcomitans and F. nucleatum, both in co-infection studies and when fibroblasts were pre-treated with the commensal before pathogen stimulation (MacDonald et al., 2021). Notably, the tested S. salivarius strains did not elicit enhanced pro-inflammatory cytokine secretion or microbiome alterations in healthy volunteers when administered in the form of a chewing gum and therefore might be interesting candidates for a probiotic therapy of periodontal disease (MacDonald et al., 2021).

The capacity of oral streptococci to modulate the tissue response to oral pathogens has also been discussed in the context of probiotic treatment of oral biofilm disease. Detected solely in samples from caries- and periodontitis-free patients, the rather recently discovered Streptococcus dentisani might be a potential candidate probiotic agent (Esteban-Fernández et al., 2019 ; Ferrer et al., 2020 ). In vitro studies showed that S. dentisani induced secretion of anti-inflammatory cytokine IL-10 in gingival fibroblasts, reduced the pro-inflammatory response to P. gingivalis and F. nucleatum, and inhibited growth as well as colonization of fibroblasts by these Gram-negative bacteria (Esteban-Fernández et al., 2019). This highlights the role of oral streptococci in maintaining oral health through their interaction with the host immune system and exertion of antagonistic effects towards pathogenic species.